Aralkyl-alcohol peiperazine derivatives adn their uses as antidepressant

ABSTRACT

Aryl alkanol piperazine derivatives of the formula  
                 
and pharmaceutical compositions comprising the same. Also disclosed are methods for treating depression using the pharmaceutical compositon. Compounds of the invention have excellent dual inhibitory actions to the uptake of the mono-amines neurotransmitter, good antidepressant activities and minor side effects.

FIELD OF INVENTION

The present invention relates to aryl alkanol piperazine derivatives and their applications as antidepressants.

TECHNICAL BACKGROUND

Depression is one of the most common mental diseases. The incidence of this disease is about 5% of the world's population and it seriously affects our health and daily life. It is predicted that by 2020, depression will become the second most deadly illness that bothers our well-being and shortens our life span (second only to ischemic heart diseases.)

Although many antidepressants have been used clinically, many patients still suffer from depression after treatment because of the poor efficacy and latent side effects of some drugs. For many patients, electricity convulsion treatment remains necessary. Therefore, the development of antidepressants is definitely among the top popular topics in new medicine research. Many pharmaceutical companies invest massive funds into developing better antidepressants. The pathogenesis of depression is unknown, but is thought to be related to transmission impediment of 5-Hydroxytrypta mine (5-HT) and noradrenalin (NA) at synapses in the brain. Taking this point into consideration, the research of antidepressants usually focuses on enhancing the transmission function of NA and 5-HT at synapses in the brain. Due to many side effects of traditional TCA antidepressants, it will eventually be replaced by selective serotonin-reuptake inhibitors (SSR1) and other new generations of antidepressants. In the past 20 years, the appearance of SSR1, represented by fluoxetine, made a big progress in the treatment of depression. The main advantages of this kind of antidepressants are fewer side effects, convenient ad ministration, and better tolerance; therefore, it is usually chosen as the first-line treatment to most patients suffering from depression. Reboxetine, which was marketed for the first time in 1997 in the United Kingdom, is the first drug of selective Norepinephrine-reuptake Inhibitors (NARI). This drug has better tolerance and better effects than SSRI in the treatment of depression. Another kind of new medicine is NA and specific 5-HT antidepressants such as Mirtazapine and Mianserine. These medicines involve both serotonergic and noradrenergic enhancement through blockade of the α2-autoreceptor and α2-heteroreceptor, increasing the release of NA and 5-HT in the synapses. American Home Products, Inc. (AHP) released a new antidepressant drug under the tradename Venlafaxine in 1997, which is the first one that is capable of inhibiting both NA and 5-HT reuptake (SNRI). Its characteristic is its rapid pharmacodynamic response. This is significant because slow response is seen as concern in other modern antidepressants. Venlafaxine has shown to be effective at treating severe and chronical depression. Compared with SSRI, the understanding of the SNRI compounds is limited.

Although different types of antidepressants have their own merits, it seems that there is no such drug that is particularly effective. Improvement is only made on their tolerance; and most of them have strong inhibitory actions to the cytochrome P450 system. Therefore, the antidepressants on the market today still cannot satisfy the need of treating depression. Many companies are studying different 5-HT subtype acceptor inhibitors. In addition, the launch of dual-acting antidepressants have prompted efforts to develop new antidepressants having triple actions on 5-HT, NA and DA systems.

DESCRIPTION OF THE INVENTION

The first aspect of the present invention provides aryl alkanol piperazine derivatives that overcome the defects of the existing antidepressants, such as insufficient antidepressant activity and strong antagonism to the cytochrome P450 system, to satisfy the needs of depression treatment.

The second aspect of the present invention provides methods of using the above compounds as antidepressants.

The aryl alkanol piperazine derivatives described in the present invention are free base or salts of the compounds represented by the following general formula:

in which the salts are one of hydrochloride, hydrobromide, sulfate, trifluoroacetate or methanesulfonate etc. Preferably the salt is hydrochloride or hydrobromide, and can contain about 0.5-3 molecules of hydrate water.

Wherein

-   -   Ar₁ and Ar₂ independently represent:         each of R₁, R₂ and R₃ can represent any one of hydrogen, a C₁-C₃         alkyl group, a C₅ or C₆ cycloalkyl group, a phenyl, substituted         phenyl, hydroxyl, methoxy, ethoxy, amino, substituted amino,         halogen, carboxylic, carboxylic ester, nitryl or acetonitrile         group.

R₁, R₂ and R₃ preferably represent one of hydrogen, a C₁-C₃ alkyl group, a hydroxyl, methoxy, ethoxy, amino, substituted amino, halogen or nitryl group.

Y represents one of C, N, or O.

Z represents a five or six-member ring containing at least one of C, S, N or O; and

n=0, 1, 2, 3; m=1, 2, 3.

The unsymmetrical carbons of the structure may be achiral carbon atoms or chiral ones.

The preferable compounds are as follows: IV-1 N¹-benzyl-N⁴-(phenylpropane-2-yl-3-ol)piperazine, IV-2 N¹-(4-chlorobenzyl)-N⁴-(phenylpropane-2-yl-3-ol)piperazine, IV-3 N¹-(1-phenylethyl)-N⁴-(phenylpropane-2-yl-3-ol)piperazine, IV-4 N¹-benzyl-N⁴-[2-(4-chlorophenyl)ethyl-2-ol]piperazine, IV-5 N¹-(3-pyridylmethyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-6 N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-7 N¹-benzyl-N⁴-[2-(4-nitrophenyl)ethyl-2-ol]piperazine, IV-8 N¹-benzyl-N⁴-[(1,2-diphenyl)ethyl-2-ol]piperazine, IV-9 N¹-(4-nitrobenzyl)-N⁴-[2-(4-acetamidophenyl)ethyl-2- ol]piperazine, IV-10 N¹-benzyl-N⁴-[2-(4-acetamidophenyl)ethyl-2-ol]piperazine, IV-11 N¹-(4-fluorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2-ol]piperazine, IV-12 N¹-[1-(4-nitrophenyl)ethyl]-N⁴-(2-phenylethyl-2-ol)piperazine, IV-13 N¹-(3-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-14 N¹-(2-nitro-5-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-15 N¹-[1-(4-nitrophenyl)ethyl]-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, IV-16 N¹-benzyl-N⁴-[2-(5-chloro-6-methoxy-2-naphthyl)ethyl-2- ol]piperazine, IV-17 N1-(3-chlorophenyl)-N4-[1-(5-chloro-6-methoxyl-naphthalen-2- yl)-propane-2-yl-1-ol]piperazine, IV-18 N1-(2-phenylethyl-2-ol)-N4-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-19 N1-benzyl-N4-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)- propane-2-yl-1-ol]piperazine, IV-20 N1-(4-nitrobenzyl)-N4-[1-(5-chloro-6-methoxyl-naphthalen-2- yl)-propane-2-yl-1-ol]piperazine, IV-21 N1-(4-aminobenzyl)-N4-[1-(5-chloro-6-methoxyl-naphthalen- 2-yl)-propane-2-yl-1-ol]piperazine, IV-22 N1-(3,4,5-trimethoxybenzyl)-N4-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-23 N¹-(4-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-24 N¹-(4-methoxybenzyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-25 N¹-(4-methoxybenzyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-26 N¹-(4-nitrobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-27 N¹-(4-nitrobenzyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-28 N¹-(4-nitrobenzyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-29 N¹-(1-phenylethyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-30 N¹-(R-1-phenylethyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-31 N¹-(R-1-phenylethyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-32 N¹-(S-1-phenylethyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-33 N¹-(S-1-phenylethyl)-N⁴-R-2-phenylethyl-2-ol)piperazine, IV-34 N¹-(S-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-35 N¹-(R-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-36 N¹-benzyl-N⁴-(2-phenylethyl-2-ol)piperazine, IV-37 N¹-(4-chlorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-38 N¹-(4-chlorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2-ol]piperazine, IV-39 N¹-benzyl-N⁴-[2-(4-methoxyphenyl)ethyl-2-ol]piperazine, IV-40 N¹,N⁴-di(2-phenylethyl-2-ol)-piperazine, IV-41 N¹-(4-a minobenzyl)-N4-(2-phenylethyl-2-ol)piperazine, IV-42 N¹-benzyl-N⁴-[(2-naphthyl) ethyl-2-ol]piperazine, IV-43 N¹-benzyl-N⁴-[(3-phenyl)propyl-3-ol]piperazine, IV-44 N¹-(2,4-dimethoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-45 N¹-benzyl-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-46 N¹-benzyl-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-47 N¹-(1-phenylpropyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-48 N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-49 N¹-(3,4-methylenedioxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-50 N¹-(1-phenethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, IV-51 N¹-(S-1-phenylethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, IV-52 N¹-(R-1-phenethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine.

A preferable compound is IV-19 N¹-benzyl-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine.

Their structures are shown in Table 1. TABLE 1 Code Ar₁ Ar₂ R₁ R₂ n m IV-1 Ph Ph H CH₃ 1 1 IV-2

Ph H CH₃ 1 1 IV-3 Ph Ph CH₃ CH₃ 1 1 IV-4 Ph

H H 1 1 IV-5

Ph H H 1 1 IV-6

Ph H H 1 1 IV-7 Ph

H H 1 1 IV-8 Ph Ph H Ph 1 1 IV-9

H H 1 1 IV-10 Ph

H H 1 1 IV-11

H H 1 1 IV-12

Ph CH₃ H 1 1 IV-13

Ph H H 1 1 IV-14

Ph H H 1 1 IV-15

CH₃ 0 1 0 IV-16 Ph

H H 1 1 IV-17

0 CH₃ 0 1 IV-18

H CH₃ 1 1 IV-19 Ph

H CH₃ 1 1 IV-20

H CH₃ 1 1 IV-21

H CH₃ 1 1 IV-22

H CH₃ 1 1 IV-23*

Ph H H 1 1 IV-26*

Ph H H 1 1 IV-29* Ph Ph CH₃ H 1 1 IV-34 Ph

(S)CH₃ CH₃ 1 1 IV-35 Ph

(R)CH₃ CH₃ 1 1 IV-36 Ph Ph H H 1 1 IV-37

Ph H H 1 1 IV-38

H H 1 1 IV-39 Ph

H H 1 1 IV-40

Ph H H 1 1 IV-41

Ph H H 1 1 IV-42 Ph

H H 1 1 IV-43 Ph Ph H H 1 2 IV-44

Ph H H 1 1 IV-45* Ph Ph H H 1 1 IV-47 Ph Ph CH₂CH₃ H 1 1 IV-48

Ph H H 1 1 IV-49

Ph H H 1 1 IV-50* Ph

CH₃ H 1 1 *a racemic compound and its corresponding optical isomers

The compounds in this invention can be prepared as follows:

Piperazine is used as a starting material to prepare the above-mentioned compounds. First, piperazine is reacted with the corresponding halogenated arylalkane through the nucleophilic substitution reaction using phase transfer catalysis to produce the N-monoalkylated compound (II). The reaction is carried out using hexadecyl trimethyl bromoa mine (CTAB) as a phase transfer catalyst, benzene/water is the solvent system, and KOH for alkylation on one N atom of the piperazine ring, with a yield of 86%.

Compound (II) is alkylated at N⁴ with the corresponding halogenated aralkylketone through the hydrocarbylation reaction to obtain the aralkylketone piperazine (III). When using K₂CO₃/DMF, the reaction can take place at room temperature, and the yield is about 80%. If using K₂CO₃/CH₃COCH₃, NaHCO₃/C₂H₅OH or Et₃ N/CHCl₃ as reaction systems, it needs reflux for 8-24 h, the color of reaction will darken as time passes, and prolonged reaction will reduce the quality and yield of the products. The main intermediate (III) can be obtained by the above mentioned processes.

Finally, the compound (III) is reduced with KBH₄ in CH₃OH under reflux for 3-5 hours to give the corresponding aryl alkanol piperazine compound (IV), which also can be prepared directly from compound (II) by step c. The goal compounds IV-1 to IV-52 are obtained by the above mentioned procedures.

The halogenated arylalkane and the halogenated arylformoxylalkyl compounds in steps a, b and c can be obtained commercially, and also be prepared by using bro mine or copper bromide with corresponding aralkyl ketones according to published conventional methods.

The aryl alkanol piperazine derivatives described in this invention have dual inhibitory actions on 5-HT and NA reuptake, and they can be used as antidepressant.

Pharmaceutical compositions comprising the derivatives described in this invention can be ad ministered to depression patients orally or via injection and so on.

The pharmaceutical composition may comprise an effective amount of a compound of the invention with one or more pharmaceutically acceptable carriers.

The carriers mentioned above include dilutents, excipents (water, etc), adhesives (fibrin derivatives, gelation, polyvinyl, pyrrolidone, etc), filling materials (starch, etc), disitegrants (calcium carbonate, sodium bicarbonate, etc) and other auxiliary materials like flavor and edulcorant.

For oral ad ministration, the compounds can be prepared as solid formulations, such as tablets, powders or capsules. For injection, they can be prepared as a liquid form.

Each formulation of the compositions in this invention may be prepared by pharmaceutically conventional methods, and the content of the active compound may be 0.1-99.5%.

The dosage of the compounds could be regulated according to various taking methods, the age and the weight of patients, and specific cases of diseases. Daily whole dosage can be 5-30 mg/kg (po) or 1-10 mg/kg (iv).

The derivatives in this invention demonstrated the antagonism to depression in the animal trials.

The inventors discover that derivatives of the present invention have a broader indication, a smaller side effect, a lower toxicity, and a slighter nerve side effect than the single action mechanism antidepressants used clinically at present like Desipra mine and Fluoxetine.

EXAMPLES General preparation 1: N-aralkyl piperazine dihydrochloride (II)

A mixture of piperazine hexahydrate (350 mmol), solid KOH (100 mmol) and CTAB (Hexadecyl Trimethylammonium Bromide, 1 mmon) in water (18 ml) was heated to get a solution. Thereafter, aralkyl chlorine (100 mmol) in 140 ml of benzene was added to the solution dropwise at 70° C., and refluxed for 1-3 h. The organic layer was washed with water and saline, dried (mgSO₄), filtered and evaporated, the residue was dissolved by 50 ml of ethanol and adjusted to PH=3 with HCl/C₂H₅OH, and the resulting precipitate was recrystallized from ethanol to obtain N-aralkyl piperazine dihydrochloride (55-86%).

General preparation 2: N¹-aralkyl-N⁴-arylformoxylalkyl piperazine dihydrochloride (III)

A mixture of N-aralkyl piperazine dihydrochloride (II) (10 mmol), halogenated aralkylketone (12 mmol), potassium iodide (1 mmol) and anhydrous K₂CO₃ (35 mmol) in DMF (50 ml) was stirred at 25° C.-50° C. for 8-12 hour, filtrated, and then evaporated to dryness, 50 ml of water was added to the residue, and extracted with EtOAc (100 ml×30). The combined organic layer was washed with saline, dried (mgSO₄). Filtered and evaporated, the residue was dissolved by 30 ml of ethanol and then adjusted to pH=2 with HCl/C₂H₅OH (5N); the resulting precipitate was recrystallized from ethanol or CH₃OH to obtain the title compound (III) (60-85%).

General preparation 3: N¹-aralky-N⁴-arylalkanol piperazine dihydrochloride (IV)

A mixture of N¹-aralkyl-N⁴-arylformoxylalkyl piperazine dihydrochloride (III) (3.5 mmol) and KHCO₃ (8.75 mmol) in methanol (60 ml) was added KBH₄ (14 mmol), and stirred at room temperature for 2 h, and then refluxed for 3-5 hours. Adjusted to a PH of 8 by 1 N aqueous NaOH and then filtered. The filtrate was extracted with EtOAC (40 ml×30), washed with saline, evaporated to dryness, which was dissolved in 20 ml of ethanol, and adjusted to PH=2 with HCl/C₂H₅OH (5N), the resulting precipitate was recrystallized from ethanol to obtain the title compound (60-80%).

Example 1 IV-1 N¹-benzyl-N⁴-(phenylpropane-2-yl-3-ol) piperazine dihydrochloride

A mixture of N-benzylpiperazine dihydrochloride (7 mmol) and 2-bromo-1-phenylpropan-1-one (8.4 mmol) was treated according to the general preparation 2 to obtain N¹-benzyl-N⁴-(1-benzoylethyl) piperazine dihydrochloride (2.6 g, 5 mmol), which was reduced according to the general preparation 3 to obtain 1.28 g of the title compound, yield 67%, mp 244-246° C.).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C, 62.68; H, 7.49; N, 7.18); theoretical value (% C, 62.66; H, 7.36; N, 7.31).

IR (KCl): ν 3240, 2980, 1450, 1030

¹HNMR (DMSO-d₆): δ0.99 (m, 3H, NCHCH₂), 3.44-3.92 (m, 9H, N—CH, piperazine-H), 4.40 (s, 2H, PhCH₂), 5.52 (br, 1H, PhCHOH), 7.24-7.67 (m, 10H, ArH).

MS: m/z 311, 221, 204

Example 2 IV-2 N¹-(4-chlorobenzyl)-N⁴-(phenylpropane-2-yl-3-ol) piperazine dihydrochloride

First of all, a mixture of 4-chlorobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-chlorobenzyl) piperazine dihydrochloride, yield 65%, mp 278-280° C. Then, a mixture of the above product (5 g, 20 mmol), KHCO₃ (70 mmol) and 2-bromo-1-phenylpropan-1-one (3.96 ml, 26 mmol) in 40 ml of ethanol was refluxed for 8 hours, and then treated according to the general preparation 2 to obtain 6.1 g of N¹-(4-chlorobenzyl)-N⁴-(1-benzoylethyl) piperazine dihydrochloride, yield 59.51%, mp 260-262° C. Finally, a mixture of above compound (1.5 g, 3.45 mmol) and KBH₄ (0.74 g, 14 mmol) was treated according to the general preparation 3 to obtain the title compound, yield 65%, mp. 240° C.).

Elementary analysis: C₂₀H₂₅ClN₂O.2HCl.2H₂O. Found: (% C, 54.74; H, 6.71; N, 6.34); theoretical value (% C, 55.12; H, 6.71; N, 6.43).

MS: m/z 344 (M)⁺

Example 3 IV-3 N¹-(1-phenylethyl)-N⁴-(phenylpropane-2-yl-3-ol) piperazine dihydrochloride

The N¹-(1-phenylethyl)-N⁴-(1-benzoylethyl) piperazine (1.42 g, 3.5 mmol) could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.86 g of the title compound, yield 62%, mp. 232-233° C.).

Elementary analysis: C₂₁H₂₈N₂O.2HCl. Found: (% C, 63.39; H, 7.65; N, 7.00); theoretical value (% C, 63.47; H, 7.61; N, 7.05).

IR (KCl)° C. ν 3260, 2960, 1480, 1020

¹HNMR (DMSO-d₆): δ 0.97 (d, J=6.6, 3H, NCHCH₃), 1.72 (d, J=7.2, 3H, PhCHCH₃), 3.46-4.00 (m, 9H, N—CHCH₃, piperazine-H), 4.63 (br, 1H, PhCHN), 5.50 (br, 1H, PhCHOH), 7.23-7.67 (m, 10H, ArH).

MS: m/z 325 (M+H)+221, 185

Example 4 IV-4 N¹-benzyl-N⁴-[2-(4-chlorophenyl) ethyl-2-ol] piperazine dihydrochloride

The N¹-benzyl-N⁴-(4-chlorobenzoylmethyl) piperazine dihydrochloride (1.2 g, 3 mmol) could be prepatated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.91 g of the title compound, yield 75%, mp. 240-242° C.).

Elementary analysis: C₁₉H₂₃ClN₂O.2HCl. Found: (% C, 56.39; H, 6.35; N, 7.00); theoretical value (% C, 56.52; H, 6.24; N, 6.94).

MS: m/z 331 (M⁺)

Example 5

IV-5 N¹-(3-pyridylmethyl)-N⁴-(2-phenylethyl-2-ol) piperazine trihydrochloride

A mixture of 3-chloromethylpyridine and piperazine hexahydrate was treated according to the general preparation 1 to obtain N-(3-pyridylmethyl) piperazine trihydrochloride (62%). A mixture of the above product (3 mmol) and 2-chloro-1-phenylethanol (3.2 mmol) was treated according to the general preparation 2 to obtain the N¹-(3-pyridylmethyl)-N⁴-phenacyl piperazine trihydrochloride (0.85 g, 2 mmol), which was reduced according to the general preparation 3 to obtain 0.61 g of the title compound, yield 72%, mp. 180-182° C.).

Elementary analysis: C₁₈H₂₃N₃O.3HCl.H₂O. Found: (% C, 51.05; H, 6.45; N, 9.95); theoretical value (% C, 50.92; H, 6.65; N, 9.89).

MS: m/z 297 (M⁺)

Example 6 IV-6 N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol) piperazine dihydrochloride

A mixture of 4-fluorobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-fluorobenzyl) piperazine dihydrochloride (67%), mp, 282-284° C. The N¹-(4-fluorobenzyl)-N⁴-phenacyl piperazine dihydrochloride could be preparated according to the general preparation 2, which was reduced with KHCO₃ (0.65 g, 6.5 mmol) and KBH₄ (0.59 g, 10.4 mmol) in methanol (40 ml) according to the general preparation 3 to obtain 0.72 g of the title compound as white solid.

Elementary analysis: C₁₉H₂₃FN₂O.2HCl. Found: (% C, 58.81; H, 6.35; N, 7.28); theoretical value (% C, 58.92; H, 6.51; N, 7.23).

MS: m/z 314 (M⁺)

Example 7 IV-7 N¹-benzyl-N⁴-[2-(4-nitrophenyl) ethyl-2-ol] piperazine dihydrochloride

The N¹-benzyl-N⁴-(4-nitrophenacyl) piperazine dihydrochloride (0.84 g, 2 mmol) could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.60 g of the title compound, yield 70%, mp. 238-241° C.).

Elementary analysis: C₁₉H₂₃N₃O₃.2HCl.½H₂O. Found: (% C, 54.05; H, 6.25; N, 9.85); theoretical value (% C, 53.91; H, 6.19; N, 9.93).

MS: m/z 314 (M⁺)

Example 8 IV-8 N¹-benzyl-N⁴-[(1,2-diphenyl) ethyl-2-ol] piperazine dihydrochloride

The N¹-benzyl-N⁴-(1-phenylbenzoylmethyl) piperazine dihydrochloride (2 g, 4.5 mmol) could be preparated according to the general preparation 2. A mixture of the above compound, KHCO₃ (10 mmol) and KBH₄ (10.4 mmol) in methanol (40 ml) was treated according to the general preparation 3 to obtain 1.2 g of the title compound as white solid, mp. 256-258° C.

Elementary analysis: C₂₅H₂₈N₂O.2HCl.H₂O. Found: (% C, 65.04; H, 6.80; N, 5.67); theoretical value (% C, 64.79; H, 6.96; N, 6.05).

MS: m/z 372 (M⁺)

Example 9 IV-9 N¹-(4-nitrobenzyl)-N⁴-[2-(4-acetamidophenyl) ethyl-2-ol] piperazine dihydrochloride

A mixture of 4-nitrobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-nitrobenzyl) piperazine dihydrochloride, yield 64%, mp 242-244° C. The N¹-(4-nitrobenzyl)-N⁴-[(4-acetamido) phenacyl] piperazine dihydrochloride (0.75 g, 1.5 mmol) could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.61 g of the title compound, yield 80%, mp 150-151° C.).

Elementary analysis: C₂₁H₂₆N₄O₄.2HCl.2H₂O. Found: (% C, 49.55; H, 6.25; N, 11.15); theoretical value (% C, 49.71; H, 6.36; N, 11.04).

MS: m/z 372 (M⁺)

Example 10 IV-10 N¹-benzyl-N⁴-[2-(4-acetamidophenyl) ethyl-2-ol] piperazine dihydrochloride

The N¹-benzyl-N⁴-[(4-acetamido) phenacyl] piperazine dihydrochloride could be synthesized according to the general preparation 2, and then reduced according to the general preparation 3 to obtain the title compound, yield 75%, mp 144-146° C.

Elementary analysis: C₂₁H₂₇N₃O₂.2HCl.2H₂O. Found: (% C, 54.35; H, 7.20; N, 9.15); theoretical value (% C, 54.54; H, 7.19; N, 9.08).

MS: m/z 353 (M⁺)

Example 11 IV-11 N¹-(4-fluorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2-ol] piperazine dihydrochloride

The N¹-(4-fluorobenzyl)-N⁴-(4-chlorophenacyl) piperazine dihydrochloride (0.87 g, 2 mmol) could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.65 g of the title compound, yield 76%, mp 236-238° C.).

Elementary analysis: C₁₉H₂₂ClFN₂O.2HCl.½H₂O. Found: (% C, 53.05; H, 5.75; N, 6.65); theoretical value (% C, 52.98; H, 5.85; N, 6.50).

MS: m/z 348 (M⁺)

Example 12 IV-12 N¹-[1-(4-nitrophenyl)ethyl]-N⁴-(2-phenylethyl-2-ol) piperazine dihydrochloride

The N¹-[1-(4-nitrophenyl)ethyl]-N⁴-phenacyl piperazine dihydrochloride was preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain the the title compound, yield 76%, mp 220-222° C.

Elementary analysis: C₂₀H₂₅N₃O₃.2HCl.H₂O. Found: (% C, 53.95; H, 6.45; N, 9.35); theoretical value (% C, 53.81; H, 6.55; N, 9.41).

MS: m/z 355 (M⁺)

Example 13 IV-13 N¹-(3-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol) piperazine dihydrochloride

The N¹-(3-methoxybenzyl)-N⁴-phenacyl piperazine (0.36 g, 1.1 mmol) could be preparated according to the general preparation 2. A mixture of above compound, KHCO₃ (0.28 g, 2.8 mmol) and KBH₄ (0.24 g, 4.4 mmol) in methanol (20 ml) was treated according to the general preparation 3 to obtain 0.24 g of the title compound as white solid.

Elementary analysis: C₂₀H₂₆N₂O₂Cl₂HCl. Found: (% C, 60.31; H, 6.93; N, 7.14); theoretical value (% C, 60.15; H, 7.07; N, 7.02).

MS: m/z 326 (M⁺)

Example 14 IV-14 N¹-(2-nitro-5-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine dihydro-chloride

The N¹-(2-nitro-5-methoxybenzyl)-N⁴-phenacyl piperazine dihydrochloride could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain the title compound, yield 72%.

Elementary analysis: C₂₀H₂₅N₃O₄.2HCl. Found: (% C, 53.98; H, 6.25; N, 9.35); theoretical value (% C, 54.06; H, 6.12; N, 9.46).

MS: m/z 371 (M⁺)

Example 15 IV-15 N¹-[1-(4-nitrophenyl) ethyl]-N⁴-[2-(4-methylphenyl)ethyl-2-ol] piperazine dihydrochloride

A mixture of N¹-[1-(4-nitrophenyl) ethyl]-N⁴-(4-methylphenacyl) piperazine dihydrochloride (2 g, 4.54 mmol), KHCO₃ (1 g, 9.99 mmol) and KBH₄ (0.98 g, 18.17 mmol) in methanol (60 ml) was treated according to the general preparation 3 to obtain 1.54 g of the title compound as white solid.

Elementary analysis: C₂₁H₂₇N₃O₃.2HCl. Found: (% C, 57.31; H, 6.63; N, 9.54); theoretical value (% C, 57.01; H, 6.61; N, 9.50).

MS: m/z 369 (M⁺)

Example 16 IV-16 N¹-benzyl-N⁴-[2-(5-chloro-6-methoxy-2-naphthyl)ethyl-2-ol] piperazine dihydrochloride

A mixture of N-benzylpiperazine dihydrochloride (2 g, 9.4 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-1-yl) ethanone (3.54 g, 11.3 mmol) and K₂CO₃ (4.55 g, 33 mmol) in acetone (120 ml) was treated according to the general preparation 2 to obtain N¹-benzyl-N⁴-(5-chloro-6-methoxy-2-naphthoylmethyl) piperazine dihydro-chloride (2.85 g). The above product (2.6 g, 30 mmol) was reduced with NaBH₄ (2.22 g, 60 mmol) in methanol (150 ml) according to the general preparation 3 to obtain 10.2 g of the title compound as white solid.

Elementary analysis: C₂₄H₂₇ClN₂O₂.2HCl. Found: (% C, 59.61; H, 6.03; N, 5.61); theoretical value (% C, 59.65; H, 6.05; N, 5.80).

MS: m/z 410 (M⁺)

Example 17 IV-17 N¹-(3-chlorophenyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine dihydrochloride

A mixture of N-(3-chlorophenyl) piperazine dihydrochloride (1.35 g, 5 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.96 g, 6 mmol) and K₂CO₃ (2.42 g, 17.5 mmol) in DMF (40 ml) was treated according to the general preparation 2 to obtain 1.65 g of N¹-(3-chlorophenyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl) ethyl] piperazine dihydrochloride, yield 64%. The above product was reduced with NaBH₄ in methanol (50 ml) according to the general preparation 3 to obtain the title compound as white solid, yield 78%.

Elementary analysis: C₂₄H₂₆Cl₂N₂O₂.2HCl. Found: (% C, 55.31; H, 5.52; N, 5.53); theoretical value (% C, 55.61; H, 5.45; N, 5.41).

MS: m/z 445 (M⁺)

Example 18 IV-18 N¹-(2-phenylethyl-2-ol)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine dihydrochloride

The N¹-phenacyl-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl] piperazine di-hydrochloride could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain the title compound, yield 70%.

Elementary analysis: C₂₆H₃₁Cl N₂O₃.2HCl. Found: (% C, 59.31; H, 6.09; N, 5.41); theoretical value (% C, 59.15; H, 6.30; N, 5.31).

MS: m/z 455 (M⁺), 129, 111

Example 19 IV-19 N¹-benzyl-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine dihydrochloride

This compound has the formula as defined in claim 1, wherein R₁ is H, R₂ is CH₃; X is CHOH; Ar₁ is phenyl, Ar₂ is 5-chloro-6-methoxy-2-naphthyl; n=m=1.

A mixture of N-benzyl piperazine dihydrochloride (1.5 g, 7.05 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl) propan-1-one (2.8 g, 8.5 mmol) and triethyl-amine (2.38 g, 23.5 mmol) in benzene (150 ml) was treated according to the general preparation 2 to obtain 2.14 g of N¹-benzyl-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl) ethyl] piperazine dihydrochloride, yield 60%, mp 252-253° C.).

To a mixture of the above product (1 g, 2 mmol) and KHCO₃ (0.5 g, 5 mmol) in methanol (50 ml) was added KBH₄ (0.44 g, 8 mmol), stirred at room temperature for 2 h, and then refluxed for 3 h, adjusted to pH=2 with 1 N aqueous NaOH and then filtered. The filtrate was extracted with EtOAC (40 ml×3), washed with saline, evaporated to dryness, which was dissolved in 20 ml of ethanol, and adjusted to pH=2 with HCl/C₂H₅OH. The resulting precipitate was recrystallized with ethanol (95%) to obtain the title compound, yield 75%. Content (HPLC): 99.80%.

Elementary analysis: C₂₅H₂₉ClN₂O₃.2HCl. Found: (% C, 58.41; H, 6.12; N, 5.51); theoretical value (% C, 58.43; H, 6.08; N, 5.45).

¹HNMR (DMSO-d₆): δ 0.97 (d, 3H, NCHCH₃), 2.81-2.93 (m, 9H, N—CHCH₃, piperazine-H), 4.02 (s, 3H, OCH₃), 5.32 (br, 1H, PhCHOH), 7.34-8.14 (m, 10H, ArH).

MS: m/z 425 (M+H)⁺, 407

Example 20 IV-20 N¹-(4-nitrobenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine dihydrochloride

The N¹-(4-nitrobenzyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl) ethyl] piperazine dihydrochloride (0.24 g, 0.5 mmol) could be preparated according to the general preparation 2, and then reduced with NaBH₄ (0.2 g, 5 mmol) in methanol (30 ml) according to the general preparation 3 to obtain 0.14 g of the title compound as white solid.

Elementary analysis: C₂₅H₂₈Cl N₃O₄.2HCl. Found: (% C, 55.25; H, 5.59; N, 7.51); theoretical value (% C, 55.31; H, 5.57; N, 7.74).

MS: m/z 470 (M⁺)

Example 21 IV-21 N¹-(4-aminobenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine trihydrochloride

A mixture of N¹-(4-aminobenzyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl) ethyl] piperazine trihydrochloride (0.08 g, 1.83 mmol) and NaBH₄ (0.1 g) in methanol (20 ml) was treated according to the general preparation 3 to obtain 0.05 g of the title compound as white solid.

Elementary analysis: C₂₅H₃₂Cl N₃O₂.3HCl. Found: (% C, 54.31; H, 6.53; N, 7.54); theoretical value (% C, 54.56; H, 6.23; N, 7.64).

MS: m/z 441 (M⁺)

Example 22 IV-22 N¹-(3,4,5-trimethoxybenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine dihydrochloride

A mixture of N¹-(3,4,5-trimethoxybenzyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl) ethyl] piperazine dihydrochloride (0.8 g, 1.4 mmol) and NaBH₄ (0.155 g, 4.1 mmol) in methanol (20 ml) was treated according to the general preparation 3 to obtain 0.19 g of the title compound as white solid, mp: 226-228° C.

Elementary analysis: C₂₈H₃₅Cl N₂O₅.2HCl. Found: (% C, 57.31; H, 6.63; N, 4.54); theoretical value (% C, 57.20; H, 6.34; N, 4.77).

MS: m/z 541 (M⁺)

Example 23 IV-23 N¹-(4-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol) piperazine dihydrochloride

A mixture of 4-methoxybenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-methoxybenzyl) piperazine dihydrochloride, yield 75%, mp. 250-252° C. The N¹-(4-methoxybenzyl)-N⁴-phenacyl piperazine dihydrochloride (0.5 g, 1.23 mmol) could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.38 g of the title compound, yield 77.55%, mp 244-246° C.).

Elementary analysis: C₂₀H₂₆N₂O₂.2HCl. Found: (% C, 59.84; H, 7.04; N, 6.83); theoretical value (% C, 60.15; H, 7.07; N, 7.02).

IR (KCl): ν 3340, 2980, 1620, 1040

MS: m/z 327 (M+H)⁺, 208, 185

Example 24 IV-24 N¹-(4-methoxybenzyl)-N⁴-(S-2-phenylethyl-2-ol) piperazine dihydrochloride

A solution of S-(+)-mandelic acid (10 mmol) in acetylchloride (30 mmol), was stirred at 25° C. for 12 hours, and then evaporated to dryness. The residue was dissolved in DMF (20 ml) and then added N-ethyl-N-isopropylpropan-2-amine (11 mmol) and C₂H₅O₂CC(CN)=NOC [N(CH₃)₂]=N(CH₃)₂BF₄ (11 mmol) at 0° C. under N₂, stirred at the same tempruture for 1 hour. Arter the addition of N-(4-methoxybenzyl)piperazine (10 mmol), the reaction mixture was stirred at 25° C. for 24 hours. and then evaporated to dryness, which was diluted in water (20 ml) and chloroform (50 ml). The organic phase was washed with water, NaHCO₃, 5% citric acid and saline (10 ml), dried (mgSO₄), filtered and then evaporated to obtain N¹-(4-methoxybenzyl)-N⁴-(1-oxo-S-2-phenylethyl-2-ol) piperazine as oil, directly used in the next step.

A mixture of above compound (50 mmol) and LiAlH₄ (125 mmol) in THF (150 ml) was refluxed for 2 hours, added Na₂SO₄ (6 g), and then stirred for 1 hour. After filtration, the filtrate was adjusted to pH=2 with HCl/C₂H₅OH, the resulting precipitate was recrystallized with ethanol to obtain the title compound, yield 75%, mp 223-224° C. [α]_(D) ²⁰+12.9 (c 1, H₂O).

Elementary analysis: C₂₀H₂₆N₂O₂.2HCl. Found: (% C, 60.23; H, 7.11; N, 6.61); theoretical value (% C, 60.15; H, 7.07; N, 7.02).

¹HNMR (DMSO-d₆): 3.57 (m, 10H, NCH₂, piperazine-H), 3.77 (s, 3H, OCH₃), 4.34 (s, 2H, PHCH₂), 5.14 (m, 1H, PhCHOH), 6.99-7.59 (m, 9H, ArH).

MS: m/z 327 (M+H)⁺, 207

Example 25 IV-25 N¹-(4-methoxybenzyl)-N⁴-(R-2-phenylethyl-2-ol) piperazine dihydrochloride

Using R-(−)-mandelic acid and N-(4-methoxybenzyl) piperazine in the similar procedure of example 24 to obtain the title compound, mp 238-239° C., [α]_(D) ²⁰−13.1 (c 1, H₂O).

Elementary analysis: C₂₀H₂₆N₂O₂.2HCl. Found: (% C, 60.34; H, 7.17; N, 6.58); theoretical value (% C, 60.15; H, 7.07; N, 7.02).

¹HNMR (DMSO-d₆): δ 3.52 (m, 10H, NCH₂, piperazine-H), 3.77 (s, 3H, OCH₃), 4.33 (s, 2H, PHCH₂), 5.14 (t, 1H, PhCHOH), 6.99-7.59 (m, 9H, ArH).

MS: m/z 327 (M+H)⁺, 207, 185

Example 26 IV-26 N¹-(4-nitrobenzyl)-N⁴-(2-phenylethyl-2-ol) piperazine dihydrochloride

The N¹-(4-nitrobenzyl)-N⁴-phenacyl piperazine dihydrochloride (0.5 g, 1.21 mmol) could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.3 g of the title compound, mp 242-243° C.).

Elementary analysis: C₁₉H₂₃N₃O₃.2HCl.½H₂O. Found: (% C, 53.84; H, 6.04; N, 10.03); theoretical value (% C, 53.90; H, 6.19; N, 9.93).

MS: m/z 342 (M+H)⁺

Example 27 IV-27 N¹-(4-nitrobenzyl)-N⁴-(S-2-phenylethyl-2-ol) piperazine dihydrochloride

Using S-(+)-mandelic acid (22 mmol) and N-benzylpiperazine (20 mmol) as starting materials to prepare N¹-benzyl-N⁴-(S-2-phenylethyl-2-ol)piperazine dihydrochloride in the similar procedure of example 24.

A mixture of the above product (1.8 g, 4.88 mmol) and 10% Pd—C (0.2 g) in HAc (40 ml) was passed hydrogen at 70% for 3 hours, and filtered then evaporated to dryness. The residue was dissolved in ethanol (20 ml), adjusted solution to pH=2 with HCl/C₂H₅OH, recrystallized with ethanol (95%) to obtain 1.14 g of N-(2S-phenylethyl-2-ol) piperazine dihydrochloride, yield 85%.

A mixture of N-(S-2-phenylethyl-2-ol) piperazine dihydrochloride (4.1 mmol) and 4-nitrobenzylchlorine (0.77 g, 4.49 mmol) was treated according to the general preparation 2 to obtain the title compound, yield 47%, mp. 214-216° C. [α]_(D) ²⁰+14.0 (c 1, H₂O).

Elementary analysis: C₁₉H₂₃N₃O₃.2HCl 1H₂O. Found: (% C, 53.02; H, 5.93; N, 7.69); theoretical value (% C, 52.78; H, 6.29; N, 7.72).

¹HNMR (DMSO-d₆): δ3.52-3.80 (br, 10H, NCH₂, piperazine-H), 4.49 (s, 2H, PHCH₂), 5.14 (m, 1H, PhCHOH), 7.28-8.32 (m, 9H, ArH).

MS: m/z 342 (M+H)⁺, 185

Example 28 IV-28 N¹-(4-nitrobenzyl)-N⁴-(R-2-phenylethyl-2-ol) piperazine dihydrochloride

Using R-(−)-mandelic acid and N-benzyl piperazine as starting materials to prepare N-(R-2-phenylethyl-2-ol) piperazine dihydrochloride in the similar procedure of example 27. A mixture of the above compound and 4-nitrobenzylchlorine was treated according to the general preparation 2 to obtain the title compound, yield 48%, mp 239-241° C. [α]_(D) ²⁰ −7.1 (c 1, H₂O).

Elementary analysis: C₁₉H₂₃N₂O₃.2HCl. Found: (% C, 54.66; H, 6.06; N, 10.09); theoretical value (% C, 55.08; H, 6.08; N, 10.14).

¹HNMR (DMSO-d₆): δ 3.52 (br, 10H, NCH₂, piperazine-H), 4.48 (s, 2H, PHCH₂), 5.14 (t, 1H, PhCHOH), 7.28-8.31 (m, 9H, ArH).

MS: m/z 342 (M+H)⁺, 207, 185

Example 29 IV-29 N¹-(1-phenylethyl)-N⁴-(2-phenylethyl-2-ol) piperazine dihydrochloride

Using N¹-(1-phenylethyl)-N⁴-phenacyl piperazine (IIV-37) (1.5 g, 3.9 mmol) as a starting material, and then reduced according to the general preparation 3 to obtain 1 g of the title compound, mp 254-255° C.).

Elementary analysis: C₂₀H₂₆N₂O₂HCl. Found: (% C, 62.43; H, 7.38; N, 7.18); theoretical value (% C, 62.66; H, 7.36; N, 7.31).

MS: m/z 310 (M⁺)

Example 30 IV-30 N¹-(R-1-phenethyl)-N⁴-(R-2-phenylethyl-2-ol) piperazine dihydrochloride (1) N-(R-1-phenethyl) piperazine dihydrochloride

A mixture of chloroacetic acid (94.5 g) and 32.2 ml of R-1-phenylethylamine in 125 ml of 8N NaOH was reacted at 70□ for 10 hours, and added a solution of BaCl₂ (65 g) in 200 ml of water dropwise, and then refluxed for 1 hour. After filtration, the solid was put into 400 ml of water and then added 100 ml of 5N H₂SO₄, refluxed for 1 hour, filtered and washed with water, the filtrate was evaporated in vacuo to give N,N-di(hydroxyformyl)-(R)-1-phenylethyla mine.

A mixture of the above product and 80 ml of formamide in 80 ml of Xylene was refluxed for 8 hours, and then extracted with EtOAC (100 ml×2). The combined organic layer was washed with water, concentrated in vacuo to obtain (R)-4-(1-phenylethyl) piperazine-2,6-dione as colorless crystals. Yield 72% (two steps).

A mixture of (R)-4-(1-phenylethyl)piperazine-2,6-dione (10.9 g, 50 mmol) and LiAlH₄ (4.75 g, 125 mmol) in 150 ml of THF was refluxed for 2 hours, and then added Na₂SO₄ (6 g), stirred for 1 hour, filtered and washed with EtOAC, the filtrate was adjusted to pH=2 with HCl/C₂H₅OH. The resulting precipitate was recrystallized from ethanol to give N-(R-1-phenylethyl) piperazine dihydrochloride, yield 85%. [α]²⁰ _(D)+22.400 (c=1, MeOH). MS: m/z 190 (M⁺).

(2) Using the above product (10 mmol) and R-(−)-mandelic acid (12 mmol) in the similar procedure of example 24 to obtain the title compound, mp 247-248° C., [α]_(D) ²⁰−18.58 (c 1, CH₃OH).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C, 62.95; H, 7.50; N, 7.23); theoretical value (% C, 62.66; H, 7.36; N, 7.31).

IR (KBr): 3260, 2970, 1460, 760, 710 cm⁻¹.

¹HNMR (DMSO-d₆): δ 1.76-1.78 (d, 3H, CH₃), 3.39-3.70 (m, 10H, NCH₂, piperazine-H), 4.55-4.61 (m, 1H, NCH), 5.13-5.16 (m, 1H, PhCHOH), 7.37-8.53 (m, 10H, ArH)

MS: m/z 311 (M+H)⁺, 207, 191, 103

Example 31

IV-31 N¹-(R-1-phenylethyl)-N⁴-(S-2-phenylethyl-2-ol) piperazine dihydrochloride

Using N-(R-1-phenethyl) piperazine (10 mmol) and S-(+)-mandelic acid (12 mmol) in the similar procedure of example 24 to obtain the title compound, mp 242-244° C., [α]_(D) ²⁰+48.72 (c 1, CH₃OH).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C, 62.75; H, 7.60; N, 7.43); theoretical value (% C, 62.66; H, 7.36; N, 7.31).

IR (KBr): 3260, 2980, 1440, 760, 710 cm⁻¹

¹HNMR (DMSO-d₆): δ 1.76-1.78 (d, 3H, CH₃), 3.40-3.73 (m, 10H, NCH₂, piperazine-H), 4.56-4.61 (m, 1H, NCH), 5.12-5.15 (m, 1H, PhCHOH), 7.38-8.53 (m, 10H, ArH)

MS: m/z 311 (M+H)⁺, 207, 191, 103

Example 32 IV-32 N¹-(S-1-phenethyl)-N⁴-(S-2-phenylethyl-2-ol) piperazine dihydrochloride

Using (S)-phenylethyla mine as a starting material to prepare N¹-(S-1-phenethyl) piperazine dihydrochloride in the similar procedure of example 30, [α]_(D) ²⁰−22.50° (c=1, MeOH). The above product (10 mmol) was reacted with S-(+)-mandelic acid (12 mmol) in the similar procedure of example 24 to obtain the title compound, mp 247-248□, [α]_(D) ²⁰ +18.21 (c 1, CH₃OH).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C, 62.38; H, 7.41; N, 7.24); theoretical value (% C, 62.66; H, 7.36; N, 7.31).

IR (KBr): 3260, 2985, 1450, 760, 710 cm⁻¹.

¹HNMR (DMSO-d₆): δ 1.76-1.78 (d, 3H, CH₃), 3.38-3.69 (m, 10H, NCH₂, piperazine-H), 4.56-4.61 (m, 1H, NCH), 5.12-5.15 (m, 1H, PhCHOH), 7.37-8.53 (m, 10H, ArH)

MS: m/z 311 (M+H)⁺, 207, 191, 103

Example 33

IV-33 N¹-(S-1-phenethyl)-N⁴-(R-2-phenylethyl-2-ol) piperazine dihydrochloride

Using R-(−)-mandelic acid (12 mmol) and N-(S-1-phenethyl) piperazine (10 mmol) in the similar procedure of example 24 to obtain the title compound, mp 230-232° C., [α]_(D) ²⁰−48.42 (c 1, CH₃OH).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C, 62.50; H, 7.49; N, 7.44); theoretical value (% C, 62.66; H, 7.36; N, 7.31).

IR (KBr): 3260, 2985, 1450, 760, 710 cm⁻¹.

¹HNMR (D₂O): δ 1.76-1.78 (d, 3H, CH₃), 3.40-3.73 (m, 10H, NCH₂, piperazine-H), 4.56-4.61 (m, 1H, NCH), 5.12-5.15 (m, 1H, PhCHOH), 7.37-8.53 (m, 10H, ArH)

MS: m/z 311 (M+H)⁺, 207, 191, 103

Example 34

IV-34 N¹-(S-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine dihydrochloride

A mixture of N¹-(S-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl) ethyl] piperazine dihydrochloride (2.55 g, 5 mmol) and NaBH₄ (1.9 g, 51 mmol) in methanol (20 ml) was treated according to the general preparation 3 to obtain 1.2 g of the title compound as white solid.

Elementary analysis: C₂₆H₃₁ClN₂O₅.2HCl. Experimental: (% C, 61.21; H, 6.63; N, 5.54); theoretical value (% C, 61.00; H, 6.50; N, 5.47).

MS: m/z 439 (M+H)⁺

Example 35 IV-35 N¹-(R-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine dihydrochloride

The title compound was prepared by using N¹-(R-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl) ethyl] piperazine dihydrochloride (2.55 g, 5 mmol) in the similar procedure of example 34.

Example 36

Tablet: The compound in this invitation 10 mg Sucrose 150 mg Corn starch 38 mg Calcium stearate 2 mg

Preparation: A mixture of the active constituent, sucrose and corn starch in water was well stirred, and then dried and sifted, which was mixed with Calcium stearate evenly, and tableted. Each tablet is 200 mg containing 10 mg of the active compound.

Example 37

Injection: The compound in this invitation 20 mg Physiological saline 80 mg

Preparation: The active constituent was dissolved in physiological saline, and then mixed evenly and filtered. The obtained clear solution was filled separately into ampoules under the aseptic condition, and the composition of each ampoule is weight of 10 mg, which containing 2 mg of the active compound.

Example 38

Antidepressant Effect of the Compounds

1. Inhibitory effects of compounds on uptaking serotonin (5-HT) and noradrenaline (NA) by brain synaptosomes:

The trial of uptaking the mono-amines neurotransmitter by synaptosomes is now one of the common method to study the central nervous pharmacology. This method is not only used to study the action mechanism of the medicament, but also to look for new antidepressant drugs which act on this tache. This method is used in the present invention, and selected Fluoxetine which is an inhibitor of 5-HT uptake and Desipra mine which is an inhibitor of NA uptake as control drugs to study the effects of invented compounds for inhibiting uptake of 5-HT and NA by brain synaptosomes. The method is recounted as follows:

(1). Preparation of synaptosomes. According to the described method by literatures (a. Biochem Pharmacol 1973, 22: 311-322, b. Methods in Neurochemistry, Vol. 2, New York: Marcel Dakker, Inc, 1972, 1-52), rats were decapitated, the brains rapidly excised, and frontal cortex dissected out on ice-cold saline (4° C.). The 3 g tissue was homogenized in 30 ml of ice-cold 0.32M sucrose and then centrifuged (1500 g) for 10 min (4° C.). The pellet was discarded and the supernatant centrifuged (20000 g) for 30 min (4° C.). After refined, the pellet was resuspended in buffer and immediately used. Protein content was deter mined with kit of total protein.

(2). Uptake of 5-HT. According to the described method by literatures (Br J Pharmacol, 1997, 122: 302-306; b. 1992, 105: 147-151), in the tubes, 1.0 ml artificial cerebral fluid, 20 μl suspension of synaptosomes and 10 μl solution of compound were added. After mixing, the tubes were incubated 5 min in 37° C. Uptake was started by addition of 10 μl [³H]-5-HT or [³H]-NA (300 nM), after another mixing, the tubes were incubated again 5 min in 37° C. The reaction was stopped by cooling the tubes in ice, the samples were then filtered through glass fibre filters and washed twice with artificial cerebral fluid. After drying in 60-70° C., the filter membranes were put into scintillation tubes. Filter-bound radioactivity was counted by scintillation spectrometry. The difference in [3H]-5-HT or [3H]-NA at 37° C. and 0° C. was taken as a measure of active uptake.

(3). Results: Under the same concentration (0.1 mmol/L for Fluoxetine and compounds), inhibited ratios of uptake 5-HT by Fluoxetine, and of uptake NA by Desipra mine count 100%, the results were setting out in Table 3. TABLE 3 Inhibitive Effects of Compounds on Brain Synaptosome Uptake of 5-HT and NA Inhibited ratio of Inhibited ratio Compounds uptake for 5-HT(%) of uptake for NA(%) IV-2 82 62 IV-4 85 51 IV-6 79 107 IV-8 <10 104 IV-11 81 101 IV-17 99 30 IV-18 127 23 IV-19 114 140 IV-20 110 108 IV-22 116 77 IV-26 63 80 IV-34 108 10 IV-35 107 58 Fluoxetine 100 Desipra mine 100

2. Antidepressant effect of compound IV-19 in vivo

Using the tail suspension test of “behavioural despair” and the mouse forced swimming test, and choosing Desipra mine as control medicament, to study the primary antidepressant effect of IV-19 that has the strong inhibited effect for both uptake of 5-HT and NA. The results are as follows:

(1). In the tail suspension test, IV-19 can diminish obviously the immobile times of mouse due to despair. The effect induced by 50 mg/kg IV-19 (20.2±16.05 sec) is the same as 10 mg/kg Desipra mine (27.5±21.93 sec), but a significant difference occurs when comparing with control (89.7±38.27).

(2). In the mouse forced swimming test, IV-19 also can diminish obviously the immobile times of mouse in water due to despair. As the results of tail suspension test, the effect induced by 50 mg/kg IV-19 (46.3±30.2 sec) is the same as 10 mg/kg Desipra mine (46±27.36 sec), but a significant difference occurs when comparing with control (93.4±27.36).

3. Acute toxicity:

LD₅₀ of VI-19 (p.o. in mice) is about 1 g/kg calculated with Bliss.

4. Bacterial reverse-mutation assay (Ames TS) of IV-19

Bacillus: S. Typhimurium TA₉₇, TA₉₈, TA₁₀₀ and TA₁₀₂

Results: The assay includes two parts of without S₉ and with S₉, in the system without S₉ TA₉₈ 5000 μg/utensil, and with S₉ TA₉₇ 5000 μg/utensil have the inhibitory effect for the growth of bacterial. The other doses haven't inhibitory effect for all bacteria, the growth of bacteria is well. All tested doses didn't induce the evident increase of revertants, Ames TS of V-19 is negative. 

1-9. (canceled)
 10. A compound of formula I:

wherein, Ar₁ and Ar₂ independently represent:

R₁, R₂ and R₃ each represents hydrogen, a C₁-C₃ alkyl group, a C₅ or C₆cycloalkyl group, a phenyl, substituted phenyl, hydroxyl, methoxy, ethoxy, amino, substituted amino, halogen, carboxylic acid, carboxylic ester, nitryl or acetonitrile group; Y represents C, N, or O; Z represents a five or six-member ring containing at least one of C, S, N or O; n represents 0, 1, 2 or 3; m represents 1, 2 or 3, in the form of a free base or a salt thereof.
 11. A compound according to claim 1, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, trifluoroacetate and methanesulfonate.
 12. A compound according to claim 11, wherein the salt is hydrochoride or hydrobromide.
 13. A compound according to claim 11, wherein the salts comprises about 0.5-3 molecules of hydrate water.
 14. A compound according to claim 10, wherein R₁, R₂ and R₃ represents independently of each other hydrogen, a C₁-C₃ alkyl, hydroxyl, methoxy, ethoxy, amino, substituted amino, halogen or nitryl group.
 15. A compound according to claim 10, in the form of a racemic mixture.
 16. A compound according to claim 10, in the form of a pure enantiomer, or a mixture of enatiomers in a non-racemic ratio.
 17. The compound of claim 1, selected from the group consisting of: IV-1 N¹-benzyl-N⁴-(phenylpropane-2-yl-3-ol)piperazine, IV-2 N¹-(4-chlorobenzyl)-N⁴-(phenylpropane-2-yl-3 -ol)piperazine, IV-3 N¹-(1-phenylethyl)-N⁴-(phenylpropane-2-yl-3 -ol)piperazine, IV-4 N¹-benzyl-N⁴-[2-(4-chlorophenyl)ethyl-2-ol]piperazine, IV-5 N¹-(3-pyridylmethyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-6 N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-7 N¹-benzyl-N⁴-[2-(4-nitrophenyl)ethyl-2-ol]piperazine, IV-8 N¹-benzyl-N⁴-[(1,2-diphenyl)ethyl-2-ol]piperazine, IV-9 N¹-(4-nitrobenzyl)-N⁴-[2-(4-acetamidophenyl)ethyl-2- ol]piperazine, IV-10 N¹-benzyl-N⁴-[2-(4-acetamidophenyl)ethyl-2- ol]piperazine, IV-11 N¹-(4-fluorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2- ol]piperazine, IV-12 N¹-[1-(4-nitrophenyl)ethyl]-N⁴-(2-phenylethyl-2- ol)piperazine, IV-13 N¹-(3-methoxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-14 N¹-(2-nitro-5-methoxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-15 N¹-[1-(4-nitrophenyl)ethyl]-N⁴-[2-(4- methylphenyl)ethyl-2-ol]piperazine, IV-16 N¹-benzyl-N⁴-[2-(5-chloro-6-methoxy-2-naphthyl)ethyl- 2-ol]piperazine, IV-17 N¹-(3-chlorophenyl)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-18 N¹-(2-phenylethyl-2-ol)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-19 N¹-benzyl-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)- propane-2-yl-1-ol]piperazine, IV-20 N¹-(4-nitrobenzyl)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-21 N¹-(4-aminobenzyl)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-22 N¹-(3,4,5-trimethoxybenzyl)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-23 N¹-(4-methoxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-24 N¹-(4-methoxybenzyl)-N⁴-(S-2-phenylethyl-2- ol)piperazine, IV-25 N¹-(4-methoxybenzyl)-N⁴-(R-2-phenylethyl-2- ol)piperazine, IV-26 N¹-(4-nitrobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-27 N¹-(4-nitrobenzyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-28 N¹-(4-nitrobenzyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-29 N¹-(1-phenylethyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-30 N¹-(R-1-phenylethyl)-N⁴-(R-2-phenylethyl-2- ol)piperazine, IV-31 N¹-(R-1-phenylethyl)-N⁴-(S-2-phenylethyl-2- ol)piperazine, IV-32 N¹-(S-1-phenylethyl)-N⁴-(S-2-phenylethyl-2- ol)piperazine, IV-33 N¹-(S-1-phenylethyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-34 N¹-(S-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-35 N¹-(R-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl- naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-36 N¹-benzyl-N⁴-(2-phenylethyl-2-ol)piperazine, IV-37 N¹-(4-chlorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-38 N¹-(4-chlorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2- ol]piperazine, IV-39 N¹-benzyl-N⁴-[2-(4-methoxyphenyl)ethyl-2- ol]piperazine, IV-40 N¹,N⁴-di(2-phenylethyl-2-ol)-piperazine, IV-41 N¹-(4-aminobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-42 N¹-benzyl-N⁴-[(2-naphthyl)ethyl-2-ol]piperazine, IV-43 N¹-benzyl-N⁴-[(3-phenyl)propyl-3-ol]piperazine, IV-44 N¹-(2,4-dimethoxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-45 N¹-benzyl-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-46 N¹-benzyl-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-47 N¹-(1-phenylpropyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-48 N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-49 N¹-(3,4-methylenedioxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-50 N¹-(1-phenethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, IV-51 N¹-(S-1-phenylethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, and IV-52 N¹-(R-1-phenethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine.


18. The compound according to claim 16, which is N¹-benzyl-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine.
 19. A pharmaceutical composition comprising a compound of claim 10, and a pharmaceutically acceptable excipient.
 20. A method for treating depression, the method comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition according to claim
 19. 